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Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene

Gene Therapy volume 18, pages 765–777 (2011)Cite this article

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Abstract

Liver cancer is a common and aggressive malignancy, but available treatment approaches remain suboptimal. Cancer targeting Gene-Viro-Therapy (CTGVT) has shown excellent anti-tumor effects in a preclinical study. CTGVT takes advantage of both gene therapy and virotherapy by incorporating an anti-tumor gene into an oncolytic virus vector. Potent anti-tumor activity is achieved by virus replication and exogenous expression of the anti-tumor gene. A dual-regulated oncolytic adenoviral vector designated Ad·AFP·E1A·E1B (Δ55) (Ad·AFP·D55 for short thereafter) was constructed by replacing the native viral E1A promoter with the simian virus 40 enhancer/α-fetoprotein (AFP) composite promoter (AFPep) based on an E1B-55K-deleted construct, ZD55. Ad·AFP·D55 showed specific replication and cytotoxicity in AFP-positive hepatoma cells. It also showed enhanced safety in normal cells when compared with the mono-regulated vector ZD55. To improve the anti-hepatoma activities of the virus, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene was introduced into Ad·AFP·D55. Ad·AFP·D55-TRAIL exhibited remarkable anti-tumor activities in vitro and in vivo. Treatment with Ad·AFP·D55-TRAIL can induce both autophagy owing to the Ad·AFP·D55 vector and caspase-dependent apoptosis owing to the TRAIL protein. Therefore, Ad·AFP·D55-TRAIL could be a potential anti-hepatoma agent with anti-tumor activities due to AFP-specific replication and TRAIL-induced apoptosis.

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Acknowledgements

We are grateful to Professor Mu-Jun Zhao for providing the EGFP-LC3 plasmid, Professor Hong-Bin Ji for providing the BEAS-2B cell line, Professor You-Cheng Xu for critical reading the manuscript, Dr Han Di for help with the molecular cloning and Ms Lan-Ying Sun for help with the cell culture. This study was supported by grants from the National Nature Science Foundation of China (No. 30623003), the Science and Technology Commission of Shanghai Municipality (No. 06DZ22032), the National Basic Research Program of China (973 Program) (No. 2004 CB51804), the Hi-Tech Research Development Program of China (863 Program) (No. 2007AA 021006), the Key Project of the Chinese Academy of Science (No. KSCX2-YW-R -09, R-04) and the Zhejiang Sci-Tech University Grant 0616033.

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Authors and Affiliations

  1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    X Cao, J-F Gu, W-D Huang, D-Q Yang, H-L Li, M Ding, N Wei, K-J Zhang, X-R Liu & X-Y Liu

  2. HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    M Yang

  3. School of Life Sciences, Guangxi Normal University, Guilin, China

    R-C Wei

  4. Laboratory of Molecular Virology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China

    Y Zeng

  5. Department of Horticulture and Garden, the Chongqing Engineering Research Center for Floriculture, Southwestern University, Chongqing, China

    H-L Li

  6. Department of General Surgery, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, China

    B Xu

  7. Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China

    Q-J Qian & X-Y Liu

  8. Laboratory of Gene and Virus Therapy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China

    Q-J Qian

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Cao, X., Yang, M., Wei, RC. et al. Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene. Gene Ther 18, 765–777 (2011). https://doi.org/10.1038/gt.2011.16

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  • DOI: https://doi.org/10.1038/gt.2011.16

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